This project delineates biochemical and pharmacological properties of sigma receptors. Sigma receptors are one-transmembrane proteins at the endoplasmic reticulum (ER) which have been shown by us to be in close prixomity to IP3 receptors on the ER. The exact biochemical role of sigma receptors is however unclear at present. In this fiscal year, we examined the potential roles of sigma receptors in regulating Ca2+ signaling in NG-108 cells by using confocal microscopy and molecular biological techniques. We found that sigma receptors regulate Ca2+ efflux at the IP3 receptors on the ER in an agonist-antagonist fashion. A 21mer antisense oligodeoxynucleotide (AS ODN) against sigma receptors blocked this action of sigma receptors. Further, we found that sigma receptors translocate from ER to the plasma membrane upon the binding of sigma receptor agonists such as (+)benzomorphan and neurosteroid. Sigma receptors also regulate Ca2+ signaling at the plasma membrane. Ca2+ influx at the plasma membrane caused by KCl-induced depolarization were regulated by sigma receptors. Again, AS ODN blocked this action of sigma receptors at the plasma membrane. We thus demonstrate that sigma receptors play important roles in Ca2+ sugnaling both at the ER and at the plasma membrane. Endogenous sigma receptor ligands such as progesterone and pregnenolone sulfate may thus modulate important cellualr functions by affecting Ca2+ signaling via sigma receptors.